Summary
I had a call with some investors earlier this week. During the call, the theme of accelerated approval came up.
I had done a blog post on the subject in September 2022 entitled: The FDA’s two leaps at once: on fast approval pathways and neurofilament light In it, I had considered that contrary to the period before 2022 when the FDA considered that the biomarker Neurofilament Light [NfL] was not known enough to base approval on, things seemed to have changed in 2022.
More recently, since December 2024, the FDA actively pushes companies to file for accelerated approval on the basis of NfL reductions.
For Alzheimer’s disease specifically, ptau-217 has now been shown to be the most reliable biomarker.
INMB’s XPro outperforms all the rest, by far, both with regards to NfL and ptau-217.
Timeline of approvals in neurodegenerative diseases
There has been a drastic uptick in drug approvals in neurodegenerative diseases in recent years. The chart below shows the timeline of drug approvals in AD and ALS since 1993.
As for Parkinson’s disease, the treatment paradigm has remained a combination of carbidopa and levodopa for decades. The year 2006 saw the approval of Azilect, a monoamine oxidase-B inhibitor. 2015 saw the approval of extended-release capsules of carbidopa and levodopa and the approval of Duopa, a gel formulation of levodopa/carbidopa. In August 2024, a long-acting oral formulation of levodopa/carbidopa going by the marketing of Crexont was approved, and two months later, a 24-hour continuous subcutaneous infusion therapy of foscarbidopa and foslevodopa by the name of VYALEV was approved.
The accelerated approval based on surrogate endpoints reasonably likely to predict clinical benefits
Introduction
The FDA explains accelerated approval as follows:
The FDA instituted its Accelerated Approval Program to allow for earlier approval of drugs that treat serious conditions, and fill an unmet medical need based on a surrogate endpoint. A surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit but is not itself a measure of clinical benefit. The use of a surrogate endpoint can considerably shorten the time required prior to receiving FDA approval.
Drug companies are still required to conduct studies to confirm the anticipated clinical benefit. If the confirmatory trial shows that the drug actually provides a clinical benefit, then the FDA grants traditional approval for the drug. If the confirmatory trial does not show that the drug provides clinical benefit, FDA has regulatory procedures in place that could lead to removing the drug from the market.”
The Accelerated Approval pathway is best fit for an approval based on biomarker evidence.
Potential biomarkers for Alzheimer’s disease
Some typical biomarkers for Alzheimer’s disease are shown below.
The FDA leading the change
Since 2020, the FDA seems to be on board with accelerated approval based on biomarkers in neurodegenerative diseases. I think there is an understanding within the FDA that, to change the treatment paradigm for neurodegenerative diseases, it is all hands on deck. After numerous years where no disease-modifying drugs have been approved in different neurodegenerative indications, the tide started turning with the accelerated approval of Aduhelm in Alzheimer’s disease based on the reduction of amyloid load in the brain.
ALS
In 2019, FDA guidance for the development of drugs for ALS still read:
In the future, greater scientific understanding of ALS may provide opportunities for discussion of surrogate endpoints that are reasonably likely to predict clinical benefit and that might serve as a basis for accelerated approval.
In 2023, at an FDA Science Forum, a poster was presented entitled ‘Evaluation of Neurofilaments as a Prognostic Biomarkers in Amyotrophic Lateral Sclerosis’. The poster concluded that neurofilaments, a marker of axonal injury and neurodegeneration, are considered promising biomarkers of ALS because of their significantly elevated levels in patients with ALS. Out of 192 investigated papers, it resulted that there was a positive correlation between ALSFRS-R total score and neurofilament (NfL and pNfH) present in plasma and CSF. In terms of disease progression, both NfL and pNfH in plasma and CSF were positively correlated with slope of disease progression. In terms of survival, higher pNfH and NfL levels were associated with a higher risk of death in ALS patients.
Alzheimer’s disease
In 2024, the FDA also updated its guidance for the development of drugs for early Alzheimer’s disease, to add support for biomarkers and surrogate endpoints. The FDA says it is now
“expected that biomarker evidence of disease will establish the reliable diagnosis of subjects in trials of early AD.”
Mostly for the earlier stages of disease, the FDA acknowledges that because of the minimal or absent cognitive and functional deficits seen in those stages of the disease, it may take longer to establish a clinically meaningful treatment effect in early AD, and assessment tools may not be sensitive enough to detect these changes. For that reason:
FDA may consider other approaches, including endpoints based on cognitive assessments or surrogate endpoints, which may allow for shorter trial durations as a basis for approval in the earliest stages of AD.” And also: “In general, even if accelerated approval is considered as the initial approval pathway, clinical outcome assessments should be included in clinical trials for early AD to assess early clinical changes that may potentially provide support for any changes observed on biomarkers.
Surrogate endpoints or intermediate clinical endpoints that do not directly measure clinical benefit but that are considered reasonably likely to predict clinical benefit may support an accelerated approval. Under the accelerated approval pathway, postapproval trials have been required to verify and describe clinical benefit. […] The acceptability of a surrogate endpoint for use in a particular therapeutic development program for early AD may depend on the stage of disease, population enrolled in trials, therapeutic mechanism of action, and availability of current treatments. […] FDA strongly supports and encourages continued research in understanding the role of biomarkers in AD and stresses the potential importance of biomarkers in the successful development of effective treatments appropriate for use in the earliest stages of AD.
Alzheimer’s: Aduhelm’s (Biogen) accelerated approval based on reduction of amyloid burden - withdrawn
Amyloid is the first hallmark of Alzheimer’s disease. Aduhelm had not shown benefit in cognition, even caused brain bleeding (microhemorrhages) or swelling (edema) in about 35% of treated patients, yet it led to reduction of amyloid. Merely on that basis, and sparked by controversy with three FDA advisors resigning and the House of Representatives calling the approval process atypical and the result of corporate greed. In 2024, Biogen finally abandoned the therapy, probably also because Medicare coverage was problematic. controversy with the FDA’s neurology division’s advisory committee being abandoned by , Aduhelm was approved.
But the precedent stands, and is actually referred to sometimes by the FDA: amyloid reduction is a surrogate endpoint predictive of benefit in Alzheimer’s disease, that allowed for the accelerated approval of Aduhelm.
I think we now know what amyloid antibodies can do: reduce cognitive decline by about 30%. That’s it. Patients won’t notice it. Families won’t notice it. Yet big pharma will, and Medicare will too.
ALS : Relyvrio’s (Amylyx) full approval - withdrawn
Amylyx’s Relyvrio was approved in the US in September 2022. The FDA had first rejected the drug, and then decided to approve it after it had received approval in Canada. The data for Relyvrio were not strong. During the approval process, the former director of the FDA’s division of neurology Billy Dunn stated that the lack of benefit Relyvrio had on NfL was a concern:
It’s something we found to be part of the overall character of data that we see that does not support robust data for the primary measurements,” Dunn said. “In the interest of having an effective medication available for ALS patients, all of us would have preferred to have seen a benefit … that we didn’t is a concern."
The same Billy Dunn had requested Amylyx to confirm that, if the drug would eventually not show a benefit in a confirmatory trial, Amylyx would take the drug off the market. Amylyx confirmed that it would. It did so in April 2024, after the drug failed in the Phoenix study.
So, Billy Dunn had been right. I was also, I think. You want to see a change in NfL values in ALS before approving a drug.
Billy Dunn meanwhile left the FDA and joined the board of Prothena.
ALS: Qalsody’s (Biogen) accelerated approval based on reduction of NfL – not withdrawn
In April 2023, the FDA approved another drug for neurodegenerative diseases via the accelerated approval pathway, namely Tofersen/Qalsody for ALS patients with an SOD1-mutation, an ultra-rare subset of ALS. The EMA followed with an approval under the exceptional circumstances pathway.
Biogen said with regards to the FDA’s approval:
Today also marks a pivotal moment in ALS research as we gained, for the first time, consensus that neurofilament can be used as a surrogate marker reasonably likely to predict clinical benefit in SOD1-ALS.
What did Qalsody show? A 55% reduction in plasma NfL compared to a 12% increase in placebo-treated participants. Additionally, levels of CSF SOD1 protein, an indirect measure of target engagement, were reduced by 35% in the QALSODY-treated group compared to 2% in the placebo group.
What was the time period? 28 weeks.
The FDA seemingly became proactive in December 2024
December 10, 2024 marks another change in the FDA’s actions, as the agency apparently became proactive, almost pushing drug developers to file for accelerated approval based on NfL values.
Clene – NfL – potential accelerated approval – ALS – MS
On December 10, 2024, tiny company Clene announced that the FDA had provided the company with a roadmap for accelerated approval in ALS through the submission of additional biomarker data. More specifically:
FDA recommends that Clene leverage additional Neurofilament Light (NfL) data from its three Expanded Access Protocols (EAPs) and the HEALEY ALS Platform Trial to support earlier presented findings
FDA recommends a follow-up meeting to discuss in more detail the analyses needed to support the accelerated approval pathway.
The FDA noted that whether NfL can serve as a reasonably likely surrogate endpoint for the effects of CNM-Au8 in ALS and whether the magnitude of change observed on NfL in patients treated with CNM-Au8 is reasonably likely to predict clinical benefit for ALS would be a matter of review.
Of note, in post-hoc analysis of its Phase 2 trial, Clene has shown a 78% reduction of risk in time to death (i.e. improved survival, presented evidence linking baseline NfL burden with a CNM-Au8 survival benefit, and evidence linking NfL decline with a CNM-Au8 survival benefit.
UniQure – NfL – potential accelerated approval – Huntington’s
Also on December 10, 2024, uniQure announced that the FDA had detailed to them what can get treatments for Huntington’s disease across the finish line - positive changes in cUHDRS and improvements in NfL levels. In that framework, UniQure also used a new measure of testing: not the less sensitive Total Functional Capacity scale, but the more precise cUHDRS.
The FDA agreed that levels of NfL can be used as a metric for therapeutic benefit. Uniqure had previously shown a 80% slowing of disease progression in the cUHDRS scale at 24 months , and statistically significant lowering of CSF NfL compared to baseline over the same time period. Patients treated with AMT-130 had a mean reduction in CSF NfL of 11% compared to baseline (p=0.02) at 24 months.
INMB’s and competitors data on NfL: Xpro outperforms all
In summary, NfL is probably the best biomarker to assess progression or treatment effect across the different neurodegenerative diseases.
So where does INMB stand? I have updated my chart with data from different companies who have reported on NfL values.
XPro far outperforms the others by a large percentage. The only drug that came close to XPro’s data was Biogen’s Qalsody for SOD1-ALS. There is still a massive difference between -84% and -55%.
I have at this time excluded data of Cassava Sciences as these data are under discussion; the claim is Cassava Sciences has cherry-picked patients that had performed best, not that Cassava Sciences manipulated these data themselves. If the data as such were not manipulated, biomarker results of Cassava Sciences as they correlate with the allegedly cherry-picked patients – whose cognition improved – could be a positive indicator for what a -84% reduction could do.
Anavex did not report clearly on percentages, I believe, but the Nfl change is minor in my eyes. The change was reported not to be statistically significant.
Other companies have now reported on this biomarker, so the list is far from exhaustive. I am, for example, still awaiting data for CGTX and Annovis’ Phase 2/3 trial in Alzheimer’s.
Ptau-217 – probably the best biomarker for Alzheimer’s disease
ALZPath - Roche
Another massive change for the field of Alzheimer’s disease came in January 2024, when a paper was published entitled ‘Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology’.
Ptau-217 is now considered the biomarker of excellence to track disease progression – or response to therapy – in Alzheimer’s disease.
Ptau-217 took the field by storm, so to speak. The biomarker was most known in academic circles in 2021.
XPro's 46% reduction over 3 months
INmune announced a 46% reduction of ptau-217 biomarker in September 2021.
I have not seen any other company report anything close to such percentage change.
Looking ahead
In light of recent evolutions with regards to ptau-217, I am confident that the FDA may one day consider a meaningful and statistically significant change in ptau-217 values compared to placebo under an accelerated approval pathway for the treatment of Alzheimer’s disease.
I am also confident that the FDA may one day consider a meaningful and statistically significant change in NfL values compared to placebo under an accelerated approval pathway for the treatment of Alzheimer’s disease.
Proof of such reductions could be accompanied by a meaningful effect on cognition. Meaningful as in: outperformance of anti-amyloid antibodies’ 30% slowing of cognitive decline.
Am I saying INmune Bio will get accelerated approval, or even apply for it, in case of success? No: I don’t know what’s behind the Phase 2 curtain, neither what INmune Bio thinks, nor how the FDA or any other regulator may think about such request. However, we need to be aware of the possibility, and the FDA’s thinking.
Recent evolutions are favoring the possibility to apply in case of a Phase 2 readout with biomarker data even remotely close to those of the Phase 1 trial.
The future will tell.
INMB investors server on Discord: https://discord.gg/ruDdptY6Xy
Comments